Real‐world study on the characteristics, post‐nephrectomy journey, and outcomes of patients with early‐stage renal cell carcinoma based on risk groups

Abstract Objectives To examine real‐world characteristics, journey, and outcomes among patients with locoregional, nonmetastatic renal cell carcinoma (RCC). Methods A retrospective analysis of medical records from the ConcertAI Oncology Dataset was performed on adults in the United States with newly diagnosed nonmetastatic RCC between January 2012–December 2017 who received surgical treatment, and were followed until August 2021. Patients were stratified based on the risk of recurrence after nephrectomy. Recurrence rate and survival outcomes were assessed. Results The cohort (n = 439) had a median age of 64 years, 66.1% were male, and 76.5% had clear‐cell histology. The median follow‐up time from nephrectomy was 39.3 months overall, 41.0 months for intermediate‐high‐risk patients (n = 377; 85.9%) and 24.1 months for high‐risk patients (n = 62; 14.1%). For intermediate‐high‐ and high‐risk patients, respectively, 68.4% and 56.5% had ≥1 medical oncologist visit after nephrectomy. Of 260 patients with documentation of postoperative imaging assessments, 72% were ordered by medical oncologists, and the median time from initial nephrectomy to the first scan was 110 days (intermediate‐high‐risk) and 51 days (high‐risk). Provider‐documented recurrence occurred in 223 (50.8%) patients, of whom 41.7% had ≥1 medical oncologist visit before the recurrence. Three‐year disease‐free survival (DFS), and overall survival rates were 49.4% and 80.8% (all patients): 27.7% and 64.7% (high‐risk); and 52.9% and 83.3% (intermediate‐high‐risk). Conclusions Our study reports low DFS after nephrectomy for patients with intermediate‐high‐ and high‐risk RCC. Subsequent approval and use of new and newly approved adjuvant therapeutic options could potentially delay or prevent recurrence.


| INTRODUCTION
An estimated 628,355 people living in the United States (US) have been diagnosed with renal cell carcinoma (RCC). 1 In 2023, approximately 81,800 people, representing 4.2% of all new cancer cases, were diagnosed with renal cancers, a consistent increase of about 1% annually over the last 15 years. 1,2Up to 66% of RCC diagnoses are made when the tumor is still localized, 16% of diagnoses occur when the disease is locally advanced, and 15% after distant metastasis, with 5-year survival rates of 93%, 74%, and 17%, respectively. 1][6] Surgical resection is the primary treatment approach for RCC. 7,8][10][11][12] Currently, adjuvant systemic therapies include the vascular endothelial growth factor receptor (VEGF-R) inhibitor sunitinib and the PD-1 inhibitor pembrolizumab, 9 approved by the US Food and Drug Administration (FDA), based on disease-free survival (DFS) results, in 2017 and 2021, respectively. 13,14To date, only adjuvant pembrolizumab has shown improved overall survival (OS) compared to placebo. 8,12,15he wide range of recurrence rates reported in the literature, reflecting diverse populations and surgical procedures, makes it difficult to discern which patients are at greatest risk of recurrence.Because disease recurrence is correlated with increased mortality as well as substantial healthcare utilization (HCU), 16,17 and given the limited treatment options available, it is crucial to identify those at greatest risk of post-nephrectomy recurrence.While HCU has been documented for patients receiving systemic treatment 18,19 and in the postrecurrence setting, 17 very few US real-world studies have examined the RCC patient journey in terms of frequency of visits and imaging post nephrectomy. 20Our objective was to understand the characteristics, journey, treatment patterns, and outcomes for patients with intermediate-high-and high-risk RCC undergoing nephrectomy, to inform future research priorities in the adjuvant setting.

| Study design and patients
This was a retrospective, observational study using electronic medical record (EMR) data.Eligible patients were adults (age ≥ 18 years) diagnosed with nonmetastatic RCC (stage I, II, III, or IV M0) between January 1, 2012 and December 31, 2017 to allow for the potential of a 3-year follow-up period.Patients were classified based on the American Joint Committee on Cancer TNM classification, 7th and 8th editions. 21,22Patients were required to have intermediate-high-risk (T2/N0/M0 with grade 4 cells or sarcomatoid histology; or T3/N0/M0) or high-risk (T4/ N0/M0, or any T stage with N ≥ 1) RCC at initial diagnosis, and to have received surgical treatment for RCC prior to metastatic RCC diagnosis.Patients were followed from the date of initial diagnosis until the end of the record, death, or data collection cutoff (August 19, 2021), whichever occurred first.
This chart review study involving human participants was performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.This research was reviewed and approved by the Institutional Review Board of Advarra, Columbia, Maryland.This research study was conducted retrospectively from data obtained for clinical purposes.An IRB waiver of consent was granted from Advarra.

| Data source
Data were obtained from the ConcertAI Oncology Dataset, a consolidated oncology EMR database available to ConcertAI through data sharing agreements with practices and other data providers, including principally community oncology practices, representing diverse practice locations, both rural and urban centers, within the US.In addition to structured data fields, the dataset consists of unstructured clinical information including provider kidney neoplasms, neoplasm recurrence local, nephrectomy, retrospective studies, risk factors progress notes and images containing relevant information, such as the date and type of disease recurrence, and pathology and radiology reports.

| Patient characteristics and journey
Patient characteristics included demographics and disease state data, including staging, histology, tumor grade, metastatic sites, Eastern Cooperative Oncology Group (ECOG) performance status, and comorbidities.Characterization of the patient's journey was based on the timing and utilization of RCC-related healthcare, including surgery, imaging, and oncology visits.

| Clinical outcomes
Real-world clinical outcomes were time to recurrence, recurrence rate, DFS, and OS.Time to recurrence was defined as the time from initial nephrectomy to the first recurrence.The recurrence rate is the proportion of patients with documented recurrence event (results in Figure A1).DFS was defined as the time from initial nephrectomy to the first recurrence event or death. 23OS was defined as the time from initial nephrectomy until death.Patients without a terminal event for an endpoint were censored at the last encounter date/end of medical record.

| Statistical methods
Demographic and clinical characteristics were evaluated descriptively for the overall population, and by risk cohorts.For outcomes analyses, the intermediate-high-risk cohort was further divided into subgroups based on tumor stage (T) and grade (G).We used Kaplan-Meier survival analysis methods to calculate 3-year time to recurrence, DFS, and OS rates, and, in a subset of patients diagnosed between January 1, 2012 and December 31, 2015, we examined 5-year DFS and OS rates.Cox proportional hazards regression analysis was used to evaluate risk categories associated with 5-year OS.

| Demographic characteristics by disease status
A total of 439 eligible patients with nonmetastatic RCC were identified and stratified into intermediate-high-risk (n = 377; 85.9%) and high-risk (n = 62; 14.1%) cohorts.The median follow-up time was 39.3 months, 41.0 months, and 24.1 months, overall and for the intermediate-high-and high-risk cohorts, respectively.The median (range) patient age was 64 (28-84) years, 66.1% of patients were male, and 80% were white (Table 1).Patient demographics were similar between risk cohorts, except the proportion of black/ African American patients was larger in the high-risk group (19.4% vs. 5.8%).92.9% of patients were managed in the community (vs.academic) oncology setting.
Most patients (92.9%) were initially diagnosed with stage III disease, 78.8% had Fuhrman grade 2-4 tumors (grade was unavailable for 18.7%), 76.5% had clear-cell histology (see Table A1 for histology classification), and the most common comorbidities were diabetes (16.9%) and renal disease (8.7%) (Table 1).ECOG performance status was undocumented for 74.7% of patients, while those with available data mostly had a score of 0 or 1 (22.6%).Among patients with undocumented ECOG, notes abstracted from medical records indicated that 96.0% had a nonimpaired performance status.

| Patient journey
After receiving a diagnosis of RCC, 92.7% of patients received a radical nephrectomy (Table 2).Following nephrectomy, 66.7% of patients have a record of at least 1 follow-up medical oncologist visit, which occurred after a median of 265.0 days.The follow-up visit occurred sooner among high-risk than intermediate-high-risk patients (median 64.0 vs. 351.5 days).High-risk patients also had more follow-up medical oncologist visits per year (median 4.7 vs. 2.3).Only 260 (59.2%) patients (60.2% of intermediate-highand 53.2% of high-risk patients) had post-nephrectomy imaging records available.72.0% of imaging studies (n = 1783) were ordered by a medical oncologist and 19.1% by a urologist (Table 2).The median time from nephrectomy to the first follow-up imaging assessment was 110.0 days for intermediate-high-and 51.0 days for high-risk patients, and the most common imaging modality was CT (56.0%) followed by MRI (18.9%) and PET (18.2%).
Only 26 (5.9%) patients initiated adjuvant systemic therapy within 90 days of the initial nephrectomy, including 21 (5.6%) intermediate-high-and 5 (8.1%) high-risk patients (Table 2).The most prescribed systemic agent was pazopanib (48.4%) followed by sunitinib (25.6%) (Table A2).initial nephrectomy (Table 3).Of those who experienced a recurrence, 42% (93/223) attended a medical oncology visit between nephrectomy and recurrence (Table A3).Among patients with a recurrence, 85.2% had distant metastasis, most commonly in the lungs (12.6%) and liver (5.3%); the metastatic site was undocumented for 74.2% of patients (Table 3).Kaplan-Meier plots for DFS and OS are presented in Figure 1.Among patients with at least 3 years of follow-up (n = 439), median DFS and OS were 35.3 and 78.9 months, respectively.The 3-year DFS rate was 49.4% and approximately 80% of patients were alive after 3 years (Figure 2).For high-risk patients, the median DFS was 13.5 months, the median OS was 53.1 months, and the 3year DFS and OS rates were 27.7% and 64.7%, respectively.The corresponding figures for the intermediate-high-risk patients were 37.6 months median DFS, 82.2 months median OS with a 52.9% 3-year DFS and 83.3% 3-year OS rate.A breakdown by intermediate-high subgroup can be seen in Figure 2.

| Outcomes after initial nephrectomy
Among patients with at least 5 years of follow-up (n = 239), the median 5-year DFS was 36.3 months, ranging from 14.6 to 39.0 months for the high-and intermediatehigh-risk groups.The 5-year DFS rate was 37.1% overall, 17.0% and 39.9% for the high-risk and intermediate-highrisk groups, respectively (Figure 3).A Cox regression analysis of 5-year OS revealed that, after controlling for age, sex, race, histology, and ECOG, patients with a recurrence were 2.4 times more likely to die within 5 years of initial nephrectomy compared to patients without recurrence (Hazard ratio [HR] = 2.43; 95% confidence interval [CI]: 1.51-3.91).The only other factor significantly associated with 5-year OS was increased age at initial RCC diagnosis (HR = 1.03; 95% CI: 1.01-1.05)(Table 4).

| Outcomes by RCC histology: Clear cell versus nonclear cell/other
Three-year recurrence rates were 46.4% and 56.1%, for ccRCC and non-ccRCC/other, respectively (Table 5).Assessments of DFS and OS showed median DFS was 37.1 months for patients with ccRCC (n = 336) compared with 20.6 months for non-ccRCC/other (n = 103), while median OS was 82.2 versus 72.8 months, respectively (Table 5).The 3-year DFS rate was 51.3% for patients with ccRCC compared to 43.2% for patients with non-ccRCC/other.The 3-year OS rates were 82.4% and 75.7% for patients with ccRCC and non-ccRCC/other, respectively.

| DISCUSSION
Results of this real-world analysis of patients initially diagnosed with nonmetastatic RCC in the US clinical setting extends our knowledge about risk categories affecting the prognosis for patients.We confirmed the overall prognostic value of tumor-specific risk classification, as over half of the patients in the population experienced a disease recurrence at some point during post-nephrectomy follow-up, and the recurrence rate was higher in the highrisk cohort as well as among patients with non-ccRCC/ other.The overall 3-year DFS rate of 49.4% observed in population. 17Such nontrivial recurrence rates observed from varied data sources support the potential benefits of adjuvant treatment capable of preventing or delaying recurrence in early-stage RCC patients.Finally, our finding of a median OS of almost 79 months aligns with recently published OS results from the KEYNOTE-564, where median OS had not been reached at 70 months postrandomization. 15,25urrent and previous data have suggested important links between RCC severity, recurrence, and prognosis in patients with locoregional disease.Our observation of over half the patients in our risk-enriched study population experiencing a recurrence is consistent with previous findings suggesting that up to 40% of patients with locoregional RCC will recur after surgery, depending on disease stage, severity, and histology, among other factors. 10,11Taken together with our other finding that among patients with at least 5 years of follow-up, recurrence is the most important driver of mortality, this highlights the importance of recurrence prevention after nephrectomy.
Our patient journey assessment showed that most patients underwent nephrectomy after RCC diagnosis without delay, but the data also suggest that there may have been potential care gaps post nephrectomy.However, the gaps noted in this study might be due to missing data F I G U R E 2 Kaplan-Meier analysis of 3-year DFS and OS from initial nephrectomy following nonmetastatic RCC, overall and by risk category. 1Subgroups do not sum to 377, 22 patients had provider documentation of risk group but no documentation of size (T) and/ or tumor grade (G).CI, confidence interval; DFS, disease-free survival; G, Fuhrman tumor grade; NR, not reached; OS, overall survival; RCC, renal cell carcinoma; T, tumor stage.as services received outside of participating practices might not have been captured: there was no record of a post-nephrectomy follow-up medical oncology visit for one-third of patients, and only 42% of those who would eventually experience a recurrence attended an oncology visit between nephrectomy and recurrence.Also, fewer than 60% of patients had records of follow-up imaging post nephrectomy despite the 2014 NCCN Guidelines® recommending imaging every 3-6 months for 2-3 years (based on stage of disease), followed by annual imaging for another 2 years after resection. 26Current NCCN Guidelines add that imaging may continue beyond 5 years, if clinically indicated. 9Of the imaging records available, most assessments were ordered by medical oncologists, and were most frequently CT scans, followed by MRI and PET imaging.It is likely that medical oncologists ordered these studies as patients with intermediate-high or high-risk disease transfer their care from urology to medical oncology after surgery.
As much of the study period predated the availability of approved adjuvant therapies, we were not surprised to see that only 5.9% of patients received systemic adjuvant therapy.Since then, sunitinib and pembrolizumab have been approved by the US FDA (in 2017 and 2021, respectively) 13,14 and have been incorporated into the NCCN Guidelines as adjuvant treatment options: sunitinib can be prescribed for certain patients with stage III ccRCC, while pembrolizumab is a recommended option for certain patients with stage II-IV ccRCC. 9Sunitinib was approved based on improved DFS versus placebo in a phase 3 clinical trial; however, the treatment was associated with high toxicity and reduced quality of life. 27Pembrolizumab became the first immunotherapy approved based on results of the phase 3 KEYNOTE-564 trial, in which patients with locally advanced or metastatic ccRCC who received pembrolizumab after nephrectomy showed a significant increase in 24-month DFS versus placebo (HR 0.68 [95% CI: 0.53, 0.87] p = 0.002) with no detriment in patient-reported outcomes. 23The tyrosine kinase inhibitors axitinib, 28 pazopanib and sorafenib, 29 the mTOR inhibitor everolimus, 30 and immune checkpoint inhibitors nivolumab, ipilimumab, and atezolizumab 24,31,32 have also been investigated in this patient population; however, no evidence of meaningful DFS improvements with these agents have been observed to date and almost all were associated with increased toxicity. 8As the therapeutic landscape continues to evolve enhanced risk assessment and modeling based on data obtained from this and future real-world analyses will facilitate improved treatment algorithms.

| Limitations
This study shares limitations common to real-world, retrospective EMR analyses, and the results must be interpreted accordingly.Notably, the data reflect treatment practice patterns limited to US oncologist practices that provide data to the ConcertAI Oncology Dataset.Therefore, imaging assessments, procedures, or visits outside of this network may not have been captured, which could explain missing data for certain variables.
We could not reach conclusions regarding differential outcomes based on tumor grade given the small size of some subgroups.Further, patients within this dataset may differ from the general nonmetastatic RCC population in ways that may not be measurable, and patient sampling procedures may have introduced unmeasurable selection bias, and therefore, may not represent all patients with RCC in the community oncology setting.This study represents the first real-world analysis of postnephrectomy treatment patterns for resected primary RCC patients in the pre-immunooncology era.Results showed substantial 3-year recurrence rates among patients with intermediate-high-risk and high-risk RCC, comparable to those reported in KEYNOTE-564. 23Study findings confirm that the prognosis of patients with nonmetastatic RCC is influenced by a range of tumor-dependent variables, and it is hoped that judicious use of newly approved adjuvant therapies will result in more favorable long-term outcomes.
T A B L E A 2 Treatment regimens, by RCC diagnosis year and risk category.

17.0
Note: There were 38 patients with no record of a visit before or after their first recurrence.Groups are not mutually exclusive, i.e., patients with visit before and after recurrence (3) may also be included in either (1) or (2).

T A B L E A 3 % 1 ..0 2 .
First visit versus first date of recurrence.Patients with Recurrence (N = 223) n/Patients with visit before recurrence date n (%) 93 (41.7%)Mean # of visits (n) before first recurrence 17.7 Median # of visits (n) before first recurrence 4Patients with visit on or after recurrence date n visits (n) throughout follow-up period Baseline demographic and clinical characteristics, overall and by risk category.
About half (n = 223) of patients (48.5% intermediate-highand 64.5% high-risk) had a documented recurrence after T A B L E 1 Disease histology classified into clear cell, nonclear cell, or others; please see TableA1for details.Patient journey after nonmetastatic RCC diagnosis, overall and by risk category.
23,24isease histology classified into sarcomatoid versus nonsarcomatoid.cBasedonchartreview of patients for whom ECOG status was unknown.T A B L E 1(Continued)this study, based on a median follow-up of about 3 years (39.3 months), was similar to the estimated 3-year DFS reported among postsurgical patients who received placebo in the recent IMmotion010 (53.5%) and KEYNOTE-564 (62.7%) clinical trials.23,24Apreviousstudy in SEER-Medicare showed a recurrence rate of 41.8% in a similarT A B L E 2Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; SD, standard deviation.a All patients included in analysis unless sample sizes (n) provided.
Post-nephrectomy recurrence, overall and by risk category.
a Denominator based on numbers of patients who experienced a recurrence.bDenominatorbased on the numbers of patients with distant metastasis.T A B L E 3 Cox regression analysis for assessing factors associated with 5-year OS following nephrectomy a .
T A B L E 4 a Based on patients diagnosed through December 31, 2015, to allow 5 years of follow-up prior to the data cutoff date, n = 239.b Please see Table A1 for details on classification.*p < 0.05.